Molecular Genetics & Genomic Medicine最新文献

Background: Intellectual developmental disorder with autism and macrocephaly (IDDAM, OMIM #615032) is an autosomal dominant neurodevelopmental disorder characterized primarily by intellectual disability, autism spectrum disorder, macrocephaly, tall stature, gastrointestinal symptoms, and variable neurological manifestations. Most cases result from de novo pathogenic variants in CHD8.

Methods: We conducted genome sequencing through the Undiagnosed Diseases Network (UDN) in a female proband harboring a CHD8 variant of uncertain significance (VUS), whose clinical presentation was consistent with IDDAM but included atypical features such as ptosis and hearing loss. Variant pathogenicity was further evaluated using EpiSign DNA methylation analysis and structural biology modeling.

Results: Genome sequencing confirmed the CHD8 variant inherited from her father, who exhibited a subtle feature, including traits consistent with attention-deficit/hyperactivity disorder. Pathogenicity was confirmed through epigenetic signature testing (EpiSign), demonstrating characteristic methylation patterns and structural biology analysis, predicting significant protein destabilization.

Conclusion: We describe the case of IDDAM caused by a paternally inherited CHD8 variant. Our findings highlight the importance of considering parental inheritance in IDDAM diagnoses and suggest epigenetic and structural biology analyses as valuable tools for reclassifying VUS when variant pathogenicity remains uncertain.

Background: The calcium voltage-gated channel subunit alpha1 F (CACNA1F) gene-related retinal disorders have overlapping clinical symptoms and no definitive genotype-phenotype correlation, posing a challenge for diagnosis.

Methods: A comprehensive ocular examination was offered to a 6-year-old boy and his elder brother from a Chinese family. Exome sequencing and Sanger sequencing were applied to the family quads. A minigene assay was used to detect the aberrant splicing.

Results: The 6-year-old boy presented with low visual acuity, congenital nystagmus, and reduced photopic and scotopic responses in electroretinography, suggesting a clinical diagnosis of cone-rod dystrophy type 3 (CORDX3). By contrast, his elder brother merely had high myopia. A hemizygous splice-site variant CACNA1F NM_005183.4:c.4422-1G>T, inherited from their heterozygous carrier mother, was identified in the two brothers. Minigene assay showed that the variant resulted in intron 37 retaining or exon 38 skipping, leading to frameshift translation and early termination. This variant was absent from the public population databases and classified as pathogenic according to the ACMG guidelines.

Conclusion: A novel splice-site variant in CACNA1F with familial expression variability was identified. This study increases our understanding of the genotypic and phenotypic spectrum of CACNA1F-related disorders.

Background: DYNC1H1 is a critical gene implicated in neurodevelopmental and neuromuscular disorders with overlapping and variable phenotypes that challenge diagnosis.

Methods and results: Whole exome sequencing in patients presenting with motor neuron disease symptoms and a predominant pattern of lower-limb muscle weakness revealed pathogenic DYNC1H1 variants. This expands the known phenotypic spectrum to include rare features such as scapular winging and camptocormia. Clinical evaluations of affected individuals revealed features consistent with SMA-LED, reinforcing the role of DYNC1H1 in neuromuscular disorders. A review of 208 published DYNC1H1 variants highlighted significant clustering in the tail domain, primarily associated with neuromuscular conditions like SMA-LED. Approximately 28% of variants exhibited overlapping neuromuscular and neurodevelopmental features, emphasizing the diagnostic challenges posed by phenotypic overlap. These findings underscore the necessity of comprehensive clinical and genetic evaluations to address the variability observed within families and improve genotype-phenotype correlations.

Conclusion: This study reinforces the importance of DYNC1H1 in motor neuron function and its pivotal role in neurodevelopmental and neuromuscular disease mechanisms. The integration of exome sequencing in clinical practice is essential for identifying rare and novel variants, enhancing diagnostic accuracy. We recommend incorporating DYNC1H1 screening into diagnostic workflows to advance understanding and management of conditions with overlapping phenotypes.

Background: Hereditary pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease caused by variations in genes such as CSF2RA and CSF2RB, which disrupt granulocyte-macrophage colony-stimulating factor signaling and impair surfactant clearance. These defects lead to progressive surfactant accumulation in alveoli, resulting in respiratory dysfunction.

Methods: We describe a 3-year-old girl with Turner syndrome who presented with recurrent cough and dyspnea and was diagnosed with hereditary PAP. Diagnostic evaluation included high-resolution computed tomography (HRCT), lung biopsy, and whole-exome sequencing of peripheral blood cells. The patient received anti-inflammatory antibiotics and underwent therapeutic whole lung lavage via endobronchial endoscopy. A systematic literature review of CSF2RA-associated hereditary PAP was performed.

Results: HRCT demonstrated characteristic "crazy paving" patterns, and bronchoalveolar lavage fluid showed positive Periodic acid-Schiff staining. Genetic analysis identified a novel hemizygous variation in CSF2RA (NM_000402.4:c.200_204del, p.Asn67SerfsTer8), confirmed as a de novo pathogenic variant. Whole lung lavage resulted in marked clinical improvement.

Conclusions: We report the first documented case of hereditary PAP caused by the CSF2RA variant NM_000402.4:c.200_204del (p.Asn67SerfsTer8), expanding the genetic spectrum of this disease. Our findings reinforce that CSF2RA-related PAP exhibits phenotypic heterogeneity and confirm whole lung lavage as the cornerstone therapy. This case highlights the importance of genetic testing in diagnosing rare PAP subtypes.

Background: Prenatal diagnosis of X-linked hydrocephalus caused by variants in the L1CAM gene is often complicated by the identification of Variants of Uncertain Significance (VUSs). This study showcases an accelerated diagnostic workflow using artificial intelligence (AI) to rapidly interpret a novel missense variant for a family with a history of the disorder.

Methods: We performed exome sequencing (ES) on a male fetus with significant sonographic brain anomalies from a 29-year-old pregnant woman. To efficiently analyze the resulting VUSs, we used the AI tool AlphaMissense to predict their pathogenicity and prioritize them for validation. The top candidate variant was then assessed via Sanger sequencing for co-segregation across eight maternal relatives. The structural impact of the mutation was visualized using the AlphaFold 3 model.

Results: Exome sequencing identified four VUSs. AlphaMissense predicted only one, L1CAM c.1228C>G (p.His410Asp), as 'likely pathogenic'. Subsequent Sanger sequencing confirmed that this variant co-segregated perfectly with the disease phenotype in the family. Based on this strong genetic evidence, the variant was reclassified from a VUS to 'Likely Pathogenic'. Structural modeling revealed that the p.His410Asp substitution disrupts a critical salt bridge, likely compromising protein stability.

Conclusion: Our two-step approach-using AI for rapid VUS prioritization followed by targeted Sanger validation-proved to be a highly efficient strategy. It provided a definitive and clinically actionable diagnosis that facilitated genetic counseling and enabled the family to pursue Preimplantation Genetic Testing (PGT). This workflow significantly enhances the power of genomic testing in the prenatal setting.

Introduction: Meckel-Gruber syndrome (MKS, OMIM 24,900), also known as Meckel syndrome, is a rare and severe autosomal recessive disorder. The syndrome is typically characterized by a triad of occipital encephalocele, bilateral renal cystic dysplasia, and postaxial polydactyly. MKS shows significant clinical heterogeneity, which poses challenges for accurate prenatal diagnosis. Prenatal ultrasound is an important tool for detecting potential cases, but the complexity of MKS often requires additional advanced techniques such as prenatal whole-exome sequencing (WES) to provide more accurate molecular genetic evidence.

Methods: In this study, we used whole-exome sequencing (WES) to analyze the genetic causes of suspected MKS in a Chinese fetus. Sanger sequencing was used to confirm the origin of the variants. The classification of variants was carried out in accordance with the guidelines of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP).

Results: A 26-year-old pregnant woman was referred to our antenatal centre for genetic diagnosis at 13 + 5 weeks of gestation due to fetal occipital encephalocele and renal cysts detected by ultrasound. Two novel heterozygous variants, c.1047delA (p.Val351fs*1) and c.1336C>T (p.Arg446*), were identified in TCTN2. Sanger sequencing revealed that the c.1047delA (p.Val351fs*1) variant was inherited from the mother and the c.1336C>T (p.Arg446*) variant was inherited from the father. According to the ACMG/AMP guidelines, these two variants were evaluated as pathogenic.

Conclusions: This study further expands the genetic mutation spectrum of TCTN2 and is conducive to further clarifying the relationship between the genotype and phenotype of MKS8. Severe variants in the TCTN2 gene appear to be more likely to lead to MKS8. Clinically, the triad is an important basis for the diagnosis of MKS8, while other variable phenotypes of MKS8 can provide additional information for prenatal diagnosis. The combination of prenatal ultrasound and WES can provide a more comprehensive and accurate diagnosis of MKS8, which will greatly aid support for early intervention and treatment.

Background: To evaluate the utility of prenatal whole exome sequencing (WES) in cases of isolated increased nuchal translucency (NT).

Methods: Retrospective analysis of the prenatal WES results in fetuses with increased NT (≥ 3.0 mm) and normal fetal anatomy, normal karyotype, and chromosomal microarray analysis (CMA). Subgroup analysis was performed based on NT measurements.

Results: Diagnostic variants were identified in 3 of 118 fetuses (2.5%) with isolated increased NT (≥ 3.0 mm). The distribution of positive findings was as follows: NT 3.0-3.4 mm group (n = 13): 1 case (7.7%) with diagnostic genetic variants; NT ≥ 3.5 mm group (n = 105): 2 cases (1.9%) with diagnostic genetic variants (both in the NT 5.0-6.4 mm subgroup). Fisher's exact test (two-tailed) showed no statistically significant differences in diagnostic yield between: NT 3.0-3.4 mm versus NT ≥ 3.5 mm (p = 0.298); NT 3.0-3.4 mm versus NT 5.0-6.4 mm (p = 1.000); NT ≥ 3.0 mm versus NT ≥ 3.5 mm (p = 1.000).

Conclusion: Our analysis revealed a low diagnostic yield (2.5%) for prenatal WES in cases of isolated increased NT ≥ 3.0 mm. Our findings provide valuable evidence for clinical counseling, particularly when patients inquire about the likelihood of isolated findings. These data offer meaningful guidance for their decision-making process regarding further testing options.

Introduction: Rare diseases sometimes present with deceptively common symptoms, complicating diagnosis and decisions about genetic testing. While testing for rare disease offers important benefits, it also carries risks that warrant careful consideration.

Methods: We review illustrative cases of rare diseases, along with current screening and diagnostic practices, to reexamine guiding principles for genetic testing. The analysis focuses on balancing clinical utility, patient-centered care, and broader policy implications.

Results: We propose a number of recommendations to guide testing, including ruling out common causes before proceeding, ensuring the presentation is atypical for other common conditions, confirming consistency with a specific, treatable rare disease entity or group, assessing patient or family capacity for informed decision-making, and matching test invasiveness to expected diagnostic utility. Comparison with newborn screening and diagnostic testing highlights discrepancies between these principles and common practices, highlighting the difficulty of achieving consistency.

Conclusions: Establishing uniform guidelines for genetic testing remains challenging, particularly given the limited knowledge surrounding rare disorders. Coordinated efforts are needed to protect patient interests, assess the utility of diagnoses across varied contexts, and ensure that both clinical practice and policy development maximize benefits while minimizing harms.

Backgroud: To investigate the clinical features and genetic etiology of one child with Okur-Chung neurodevelopmental syndrome (OCNDS). The pathogenic variation spectrum of the CSNK2A1 gene and the phenotype spectrum of OCNDS were analyzed retrospectively.

Methods: A patient was selected from the endocrinology department of Dongying People's Hospital in July 2024. The genetic etiology of the phenotypic abnormality was identified by whole-exome sequencing (WES). All previously reported cases of OCNDS were retrieved from China National Knowledge Infrastructure (CNKI), Wanfang Data, PubMed, and the ClinVar database, and the phenotype and pathogenicity of the CSNK2A1 gene were retrospectively summarized. The differences in the mutation location and clinical phenotype of the CSNK2A1 gene were analyzed in combination with the literature on cell and molecular genetics.

Results: One variant (NM_001895.4: c.149A>G:p.Tyr50Cys) were de novo and previously reported within the CSNK2A1 gene and has been identified as a potential cause of OCNDS. The clinical data of 65 patients with OCNDS were retrospectively analyzed. The main clinical characteristics of OCNDS were developmental retardation of the nervous system, intellectual disability, facial deformity, language disorder, and other system abnormalities. This specific variant is located within the Glycine-Rich loop domain. There were significant differences in sleep disorders, autism spectrum disorders, short stature, and developmental delays.

Conclusion: This study diagnosed an OCNDS patient caused by a heterozygous mutation NM_001895.4: c.149A>G:p.Tyr50Cys in the CSNK2A1 gene through exome sequencing technology, further expanding the pathogenic variant spectrum of this gene. A systematic literature review and analysis was conducted to provide a foundation for the subsequent demonstration, which was based on the findings of the review. The demonstration revealed that variants in critical residues within the kinase domain disrupt the protein's spatial conformation and impair its function. This provides molecular evidence for genotype-phenotype correlation. These findings contribute to the advancement of knowledge in the field of OCNDS pathogenesis and provide a foundation for the development of genetic counselling and targeted therapeutic interventions.

Background: Noonan syndrome is a congenital genetic disorder characterized by distinctive craniofacial features, short stature, and congenital heart disease. Dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway is a common molecular mechanism underlying the pathogenesis of these disorders. Germline mutations in RIT1 have also been identified in patients with Noonan syndrome. Patients with RIT1 mutations frequently exhibit cardiovascular abnormalities such as hypertrophic cardiomyopathy and lymphatic disorders. However, it remains unclear when cardiovascular abnormalities and lymphatic disorders develop and whether these disorders influence prognosis during the fetal period.

Methods: We investigated the cardiovascular and lymphatic phenotypes of Rit1^A57G/+ embryos. To elucidate that the activation of MEK/ERK is the involvement of cardiac abnormalities in Rit1^A57G/+ embryos, we administered a MEK1/2 inhibitor to Rit1^A57G/+ embryos and investigated the cardiovascular phenotypes.

Results: At E16.5, Rit1^A57G/+ embryos exhibited cardiac hypertrophy without cardiomyocyte hypertrophy and demonstrated progressive cell proliferation. Furthermore, Rit1^A57G/+ embryos exhibited pulmonary valve stenosis and lymphatic vessel expansion. Maternal intraperitoneal injection of PD0325901, a MEK1/2 inhibitor, prevented cardiac hypertrophy in Rit1^A57G/+ embryos.

Conclusions: Rit1 mutation causes cardiovascular and lymphatic abnormalities in the fetal period, and that the activation of MEK/ERK is the potential pathogenesis of cardiac hypertrophy.